CN105218532B - Benzotriazole compound, preparation method and its medical usage - Google Patents

Benzotriazole compound, preparation method and its medical usage Download PDF

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CN105218532B
CN105218532B CN201510672684.4A CN201510672684A CN105218532B CN 105218532 B CN105218532 B CN 105218532B CN 201510672684 A CN201510672684 A CN 201510672684A CN 105218532 B CN105218532 B CN 105218532B
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benzotriazole
methoxyphenyls
bases
acid
acetamide
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CN105218532A (en
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陈益华
逄秀凤
胡克文
吴海刚
王洁琼
刘明耀
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East China Normal University
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East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C07D249/20—Benzotriazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a kind of a kind of benzotriazole micromolecular compound or its pharmaceutically acceptable acid-addition salts represented by structure formula (I), and the pharmaceutical composition containing such compound；The invention also discloses the medical usage of the benzotriazole micromolecular compound or its pharmaceutically acceptable acid-addition salts in the disease medicaments such as treatment various malignant growths, transfer and recurrence caused by the RAS gene mutations are prepared.

Description

Benzotriazole compound, preparation method and its medical usage
Technical field
The invention belongs to field of medicaments, and in particular to be related to small molecule benzotriazole compound, pharmaceutically may be used The salt and its medical usage of receiving.
Technical background
Cancer threatens the health of the mankind for a long time, with diabetes, cardiovascular and cerebrovascular disease and referred to as the three of human health Big killer.For cancer, current essential therapeutic arsenals are divided into surgical operation therapy, radiation and chemotherapy.Although for early stage Cancer patient, can be by the method tumor resection of operation, but to after middle and advanced stage, cancer cell will be spread, corresponding hand Art cutting method will not reach good therapeutic effect.
With the rapid development of the Human Genome Project and sequencing technologies, by carrying out full-length genome to human tumor sample Sequencing analysis, can obtain the hereditary information of Oncogenome complexity exactly, and the occurrence and development and its heredity to tumour are complicated Property obtain more understanding, and molecule parting for tumour and the personalized treatment of patient provide advantageous information.Tumour is a kind of This viewpoint of genopathy is widely accepted, and tumour is that (high frequency is mutated and low frequency is mutated by multiple related genes Gene) caused by common mutation, include activation expression and the inactivation of tumor suppressor gene of oncogene, this is also that tumour cell is unrestricted The molecular basis of growth.Although there are a large amount of different types of gene mutations in tumour cell, only a small number of gene (15-20 It is a) mutation could open tumorigenic process.In the numerous oncogene of the mankind, RAS is mutation probability highest in tumour One of gene family.RAS mutated tumors account for 1/3rd of all malignant tumours of mankind sum according to statistics, and its take place frequently in Lung cancer, in colon cancer and cancer of pancreas, this three classes tumour and breast cancer form the big lethal cancer of the mankind four together.It can be seen that RAS dashes forward It is very harmful to become tumour.
RAS albumen is the coded product of proto-oncogene RAS, is one of RAS superfamily albumen important members, is molecule Measure the monomer gtp binding protein for 20~25kDa.RAS albumen is generally in its non-activated state, RAS under normal physiological condition The activation of albumen is strictly regulated and controled, and the RAS albumen of activation is promptly restored to its non-activated state after its function is played, in order Ground regulates and controls downstream signaling pathway, so as to maintain cell normally to grow, break up.But RAS is as proto-oncogene, once it is activated Just into the oncogene with carcinogenic activity.The most common active mode of RAS genes is the missense mutation of gene, is usually occurred On 12,13 and 61 bit codons.Gene mutation causes the change of RAS protein steric structurals, RAS is held in what is combined with GTP The continuous state of activation, constantly activates downstream signaling pathway, so as to cause the proliferation out of control of cell, produces canceration.RAS gene families Three members HRAS, NRAS and KRAS, their mutation probabilities in different tumor types are not quite similar, and there is organizing specific Property, HRAS common mutations in skin (melanoma) and head and neck cancer, NRAS common mutations in Hematopoietic Malignancies, and KRAS then common mutations in colorectal cancer, lung cancer (especially non-small cell lung cancer) and cancer of pancreas.The mutation of KRAS accounts for all The 86% of RAS gene mutations, accounts for the 21.6% of all malignant tumours of the mankind.In colon cancer, KRAS mutation tumour accounts for 45%, have 35% in lung cancer, and cancer of pancreas is then up to 90%.Studies have reported that KRAS mutation can cause some specific cells Show stem cell properties, and HRAS and NRAS is without this function, this characteristic be also considered as KRAS compared with HRAS and NRAS has the possible cause of higher mutation probability in human tumor, and the mutation of KRAS genes is more conducive to the generation of cancer.
RAS genes as important oncogene self-discovery since be studied more than 30 years, its protein structure, function, Activation mechanism and upstream and downstream signal path are also increasingly clear and definite；RAS genes, especially KRAS genes, the height in human tumor are dashed forward Variability and its important impetus in tumor development become a preferable target of tumor cells targeted therapy Point, and dependence cancer gene main in tumour cell.But it clinically there is no effectively treatment RAS mutated tumors so far Micromolecular inhibitor.Therefore carry out drug development for RAS mutation and oncotherapy is of great significance.
The present invention is with grade gene cell system T29 and KT1P (KRASV12) it is screening model, passed through using lethal model is cooperateed with To innovatively finding a kind of small molecule containing benzotriazole structural framework after the bioactivity screening of a large amount of compounds Organic compound and its pharmaceutically acceptable salt have the ability that specificity suppresses RAS mutated tumor cell survivals, and herein On the basis of designed and synthesized the anticancer small numerator reactive compound of a kind of selectively targeted RAS mutation, by subsequently deeply grinding Study carefully discovery, the compounds of this invention has suppresses RAS mutation malignant growths and transfer activity well, and RAS is mutated Tumour cell also there is excellent selectivity.This kind of novel reactive compound of chemical constitution can be used for treatment due to RAS Growth and metastasis of tumours caused by mutation, and promise to be a kind of drug candidate of oncotherapy.Such compound contains Purposes of the pharmaceutical composition of such compound in preparing treatment and targeting the tumour medicine of RAS gene mutations, and be used for Prepare the various tumour occurrence and development triggered due to RAS gene mutations of prevention and treatment, including tumour growth, infiltration and transfer Purposes in medicine.
The content of the invention
First purpose of the present invention is that prevention can be used as by providing the novel benzotriazole compound of a class formation With treatment antitumor lead compound as caused by RAS gene mutations, including its pharmaceutically acceptable salt etc..
A kind of benzotriazole or benzisoxa imidazolium compounds of the composite structure of the present invention as shown in formula (I) pharmaceutically may be used The salt of receiving：
Wherein：
M and p refers to the number of chain methylene, is respectively 0,1,2,3 or 4.
N refers to the number of carbonyl, is respectively 0 or 1.
R1Refer to the substituent on phenyl ring, be derived from following groups：Hydrogen, methyl, methoxyl group, halogen, benzyloxy, cyano group, acid amides Base.
R2It is derived from following groups：Cyano group, ONO2, halogen, hydroxyl, carboxyl, methoxyl group, cyclopropane base, furyl, vinyl, Vinyl carboxyl, trifluoromethyl, 5- bromines furyl, phenyl, pyridine radicals, tolyl, methylsulfonyl phenyl, C1-C3 alkoxyl phenyls, Cyclopentyloxy phenyl, halogenophenyl, nitrobenzophenone, benzyloxy-phenyl, hydroxy phenyl.
In structural formula shown in the present invention, work as R2For substituted-phenyl, during m=0, it is represented by following structural formula (II)：
Wherein：
P refers to the number of chain methylene, is respectively 0,1,2,3 or 4.
N refers to the number of carbonyl, is respectively 0 or 1.
R1Refer to the substituent on phenyl ring, be derived from following groups：Hydrogen, methyl, methoxyl group, halogen, benzyloxy, cyano group, acid amides Base.
R3It is derived from following groups：Hydrogen, hydroxyl, methyl, halogen, C1-C3 alkoxies, cyclopentyloxy, trifluoromethyl, benzyloxy Base, nitro, mesyl.
The present invention provides benzotriazole compound or its analog or pharmaceutically acceptable salt, including：
5- bromine furans -2- carboxylic acids [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- chlorphenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- bromophenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- aminomethyl phenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (3,5- 3,5-dimethylphenyl) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- benzyloxy-phenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- acetylamino phenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- cyano-phenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- fluorophenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (3,4,5- trimethoxyphenyl) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- phenyl -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- benzyl -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [1- (3- phenyl propyls) -1H- benzotriazole -5- bases]-acid amides,
1- phenyl carboxylic acids [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
1- (2- pyridine radicals)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
1- (2,3,4- trimethoxyphenyl)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
1- (2,4- Dimethoxyphenyl)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
2- (4- iodophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- bromophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- chlorphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- fluoro-phenyls)-N- [2- (4- methoxyl groups-phenyl) -2H- benzotriazole -5- bases]-acetamide,
2- (2- bromophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- aminomethyl phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- sulfonyloxy methyls phenyl)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- nitrobenzophenones)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- methoxyphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (3,4,5- trimethoxyphenyl)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
The bromo- N- of 4- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-butyramide,
3- ((2- (4- methoxyphenyl -2H- benzotriazole -5- bases) amino) -3- Oxoacetic Acids,
The bromo- N- of 2- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
The bromo- N- of 2- [2- (3,4,5- trimethoxyphenyl) -2H- benzotriazole -5- bases]-acetamide,
2- cyano group-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- methoxyl groups-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (2- methoxy ethyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- hydroxy-ns-[2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
1- cyclopropyl-carboxylic acids-[2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
2- (4- benzyloxy-phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- hydroxy phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- isopropyl phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- propoxyphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- cyclopentyloxies phenyl)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-3- Phenylpropylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-4- methoxYbenzylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2- methoxYbenzylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2- (4- methoxyphenyl ethyls) amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2,4- Dimethoxybenzylamino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2,4,6- trimethoxy benzyl amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-4- trifluoromethyl benzyls amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-3- bromobenzyls amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2- (3,4,5- trimethoxyphenyl) ethylamino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N- (2- furfuryls) amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
The chloro- N- of 1- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
The chloro- N- of 3- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-butyramide,
3- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases carbamoyl]-acrylic acid,
Trifluoromethyl-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide, or
Nitric acid 2- ((2- (4- methoxyphenyls) -2H- benzotriazole -5- bases) amino -2- oxoethyl esters.
The invention also provides the acid-addition salts formed by the benzotriazole small molecular organic compounds with acid；It is excellent Selection of land, it is described acid for hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid, to toluene sulphur Acid, lactic acid, pyruvic acid, maleic acid, arbitrary one kind of butanedioic acid.
The invention also provides a kind of method for preparing the benzotriazole small molecular organic compounds, including it is following Step：
Method one：
(1) the 5- nitro benzotriazole of solid is produced in the presence of sodium nitrite and acetic acid by 4-nitro-o-phenylenediamine；
(2) substituted in alkaline conditions by the 5- nitros benzotriazole that step (1) obtains and various halogenated alkanes Reaction, obtains 5- nitro -2- substituent -2H- benzotriazole after separation；
(3) by the 5- nitro -2- substituent -2H- benzotriazole that step (2) obtains in iron powder (or zinc powder, magnesium powder) and Substituted 5- amino -2H- benzotriazole key intermediates are generated in the presence of hydrochloric acid (or acetic acid)；
(4) the substituted 5- amino -2H- benzotriazole key intermediate obtained by step (3) and various acid, carboxylic acid halides or Person's acid anhydrides is coupled to form the final product benzotriazole compound.
Method two：
(1) diazol is formed by various substituted aromatic amines and sodium nitrite in acid condition；
(2) the generation diazol obtained by step (1) forms azo intermediate with m-phenylene diamine (MPD)；
(3) azo intermediate obtained by step (2) generates substituted 5- in the presence of copper sulphate, ammonium hydroxide and pyridine Amino -2H- benzotriazole key intermediates；
(4) the substituted 5- amino -2H- benzotriazole key intermediate obtained by step (3) and various acid, carboxylic acid halides or Person's acid anhydrides is coupled to form the final product benzotriazole compound；
The acid is hydrochloric acid, acetic acid.
The invention also provides a kind of method for the pharmaceutically acceptable salt for preparing the benzotriazole compound, It is characterized in that, it the described method comprises the following steps：
(1) benzotriazole compounds compound is dissolved in corresponding organic solvent (methanol, ethanol, acetone, second Nitrile, ether, dichloromethane, chloroform, ethyl acetate, dioxane, glycol dimethyl ether) in；
(2) by hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid, to toluene Sulfonic acid, lactic acid, pyruvic acid, maleic acid, butanedioic acid are dissolved in corresponding organic solvent (methanol, ethanol, acetone, acetonitrile, ether, two Chloromethanes, chloroform, ethyl acetate, dioxane, glycol dimethyl ether) in；
(3) above two solution is sufficiently mixed in proportion, place 10 minutes to 8 it is small when after, solvent is removed under reduced pressure, through dry Corresponding benzotriazole compound pharmaceutically acceptable salt is obtained after dry.
Another object of the present invention is to provide such benzotriazole compound and related analogs to prepare prevention Application with treatment as the relevant disease medicine caused by RAS gene mutations.
The present invention also aims to find above-claimed cpd or pharmaceutical composition containing above-claimed cpd to be used to prepare Prevent and treat as the medicine of transfer and the recurrence of various malignant tumours and relevant tumour caused by RAS gene mutations, The malignant tumour includes lung cancer, intestinal cancer, cancer of pancreas, breast cancer, uterine cancer, multiple bone marrow cancer, stomach cancer, oophoroma, bladder Cancer, prostate cancer, cervical carcinoma, glioma etc..
The present invention also provides a kind of benzotriazole compound pharmaceutically acceptable salt, by the benzotriazole The acid-addition salts that compound is formed with acid；Wherein, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, bigcatkin willow Acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, lactic acid, pyruvic acid, maleic acid or butanedioic acid.
The present invention also provides a kind of benzotriazole compound or its pharmaceutically acceptable salt, is three nitrogen of benzo Azole compounds combine to form label with radioactive group, fluorophor or biotin.
The present invention also provides a kind of pharmaceutical composition, wherein containing benzotriazole compound of the present invention or its Pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.Pharmaceutical composition of the present invention is formulated into injectable stream Body, aerosol, emulsifiable paste, gelling agent, pill, capsule, syrup, transdermal patch or excipient.
The present invention also provides benzotriazole compound or its pharmaceutically acceptable salt to prepare prevention and treatment target Application in the neoplasm growth field of medicament of RAS gene mutations.
The present invention also provides the benzotriazole compound and related analogs or its pharmaceutically acceptable salt Application in preparing prevention and treatment and causing tumour medicine by RAS mutation.The present invention proposes the benzotriazole Compound or its pharmaceutically acceptable salt answering in suppression tumor cell proliferation, growth, migration and the medicine of infiltration is prepared With；Wherein, the tumour cell include lung carcinoma cell, breast cancer cell, colon cancer cell, pancreatic cancer cell, uterine cancer cells, Multiple cancer cell of bone marrow, stomach cancer cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, prostate gland cancer cell, cervical cancer cell, nerve Glioma cell.
The invention also provides the benzotriazole compound is preparing the medicine of prevention and treatment malignant tumour In application；Wherein, the malignant tumour include lung cancer, breast cancer, colon cancer, cancer of pancreas, uterine cancer, multiple bone marrow cancer, Stomach cancer, oophoroma, carcinoma of urinary bladder, prostate cancer, cervical carcinoma, glioma.
The invention also provides the benzotriazole compound or its pharmaceutically acceptable salt are preparing prevention With treatment Malignant tumor of bonal metastasis and the application in the medicine of recurrence；Wherein, it is thin to include lung carcinoma cell, breast cancer for the malignant tumour Born of the same parents, colon cancer cell, pancreatic cancer cell, uterine cancer cells, multiple cancer cell of bone marrow, stomach cancer cell, ovarian cancer cell, bladder Cancer cell, prostate gland cancer cell, cervical cancer cell, neuroglial cytoma.
In the present invention, benzotriazole compound or pharmaceutically acceptable salt can be used alone or and other drugs It is used in combination.
The beneficial effects of the present invention are：Relative to the inhibition of the T29 cell lines of RAS wild types, chemical combination of the present invention The T29KT1P cells that thing is mutated RAS all have very excellent activity and selectivity, and the compounds of this invention is mutated RAS Tumour cell all has obviously proliferation inhibition activity, and compared with the inhibitory activity of K-RAS wild type tumor cells Obvious selectivity is showed, difference has conspicuousness.In addition, the compounds of this invention can not only significantly inhibit K-RAS mutation The size that tumor cell clone is formed, may also suppress the number that the tumor cell clone of K-RAS mutation is formed.Even more important It is that the compounds of this invention can significantly suppress the growth of the tumour of RAS mutation, and be in dose-dependent relation.The present inventionization Compound all shows significant therapeutic effect in the tumour that K-RAS is mutated.
Brief description of the drawings
Fig. 1 show the compounds of this invention and the selective depression of RAS mutant cells (T29＆T29KT1P) proliferation activity is made With.
Fig. 2 show selective inhibitory of the compounds of this invention to RAS mutated tumor cell-proliferation activities.
Fig. 3 show the Clone formation that the compounds of this invention suppresses RAS mutated tumor cells.
Fig. 4 show the growth that the compounds of this invention suppresses RAS mutant cell xenograft tumours.
Fig. 5 show inhibitory action of the compounds of this invention to RAS genetically modified animal Model Tumors.
Embodiment：
With reference to specific examples below and attached drawing, the present invention is described in further detail, protection content of the invention It is not limited to following embodiments.Without departing from the spirit and scope of the invention, those skilled in the art it is conceivable that change Change and advantage is all included in the present invention, and using appended claims as protection domain.
1H-NMR is measured with 500 type instrument of Varian MercuryAMX300 or Bruker；MS VG ZAB-HS or VG- 7070 type instrument measure, and are EI sources (70ev) in addition to indicating；All solvents pass through re-distillation, used nothing before use Aqueous solvent is obtained by standard method drying process；In addition to explanation, all reactions are to be carried out under argon gas protection and use ripple Layer chromatography (TLC) tracks, through saturated common salt washing and anhydrous magnesium sulfate drying process during post processing；The purifying of product removes Illustrate the outer column chromatography for using silica gel (200-300 mesh)；Used silica gel, including 200-300 mesh and GF254 are Qingdao Marine chemical industry factory or the production of Yantai Yuan Bo silica gel company.
Embodiment one：The preparation of each compound
Embodiment 1-1,5- bromine furans -2- carboxylic acids [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides (RS001)
P-nethoxyaniline (2.48g, 20.14mmol) is dissolved in the aqueous hydrochloric acid solution (4M) of 48ml, in ice bath bar Sodium nitrite (1.67g, 24.17mmol) is added under part, after reacting half an hour, by Amcide Ammate (3.16g) at 0 DEG C slowly In addition system and continue to stir half an hour.The pH of solution is adjusted to 5-6 with sodium acetate, by o-phenylenediamine under condition of ice bath Hydrochloride (3.33g, 18.42mmol) is added in reaction system, is stirred overnight.TLC is detected after the reaction was complete, uses hydrogen-oxygen Change sodium solution to adjust to pH more than 14, extracted with ethyl acetate and water, merge organic phase, vacuum distillation, obtains drying Crude product azo-compound.The pyridinium dissolution of azo-compound 40ml, 60ml concentrated ammonia liquors/water is added to by 10g anhydrous cupric sulfates (v/v=1/1) in mixed solution, mixture flows back under oil bath, until the reaction is complete.
The reaction solution of cooling is added to excessive water, is extracted with ethyl acetate and water, merges organic phase, decompression is steamed Evaporate, obtained crude product benzotriazole amine is separated through column chromatography, obtains pure 2- (4- methoxyphenyls) -5- amino -2H- Benzotriazole 2.52g, yield 52%.
By 2- (4- methoxyphenyls) -5- amino -2H- benzotriazole (87mg, 0.36mmol), 5- bromine furancarboxylic acids (80mg, 0.419mmol), HOBt (70mg, 0.518mmol), EDC.HCl (104mg, 0.518mmol) are dissolved in N, N- diformazans After base formamide (DMF), it is stirred under 50-60 DEG C of oil bath, is detected with TLC, until the reaction is complete.Reaction solution adds Excessive water, is extracted with ethyl acetate and water, merges organic phase, vacuum distillation, obtains crude product, divided with column chromatography From obtaining sterling 5- bromine furans -2- carboxylic acids [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides 100mg, yield For 67%.1H NMR(DMSO,300MHz):.10.48 (s, 1H), 8.48 (d, J=1.2Hz, 1H), 8.22 (d, J=9.0Hz, 2H), 7.98 (t, J=4.5Hz, 1H), 7.75 (dd, J=1.82.1Hz, 1H), 7.44 (d, J=3.6Hz, 1H), 7.18 (d, J =9.0Hz, 2H), 6.87 (d, J=3.3Hz, 1H), 3.86 (s, 3H)
1 Compound RS 001 of table arrives the preparation method of RS057
Example 1 below -1 provides the preparation method and product detection of the compounds of this invention RS001-RS057 to 1-57 As a result.
Embodiment 1-2,5- bromine furans -2- carboxylic acids [2- (4- chlorphenyls) -2H- benzotriazole -5- bases]-acid amides (RS002) Preparation
P-nethoxyaniline is replaced as 4- chloroanilines, RS002 is prepared by the method for prepare compound RS001.1H NMR (DMSO,300MHz):δ 10.51 (s, 1H), 8.49 (s, 1H), 8.27 (d, J=8.7Hz, 2H), 8.98 (dd, J=0.3, 0.3Hz, 1H), 7.78 (t, J=0.9Hz, 1H), 7.71 (s, 2H), 7.44 (d, J=3.3Hz, 1H), 6.87 (d, J=3.3Hz, 1H).
Embodiment 1-3,5- bromine furans -2- carboxylic acids [2- (4- bromophenyls) -2H- benzotriazole -5- bases]-acid amides (RS003) Preparation
P-nethoxyaniline is replaced as 4- bromanilines, RS003 is prepared by the method for prepare compound RS001.1H NMR (DMSO,300MHz):δ 10.46 (d, 1 Η), 8.47 (d, 1 Η), 8.19 (d, J=8.7Hz, 2H), 7.97 (d, J=9.0Hz, 1H), 7.81-7.74 (m, 3H), 7.43 (d, J=3.3Hz, 1H), 6.85 (d, J=3.3Hz, 1H)
Embodiment 1-4,5- bromine furans -2- carboxylic acids [2- (4- aminomethyl phenyls) -2H- benzotriazole -5- bases]-acid amides (RS004) preparation
P-nethoxyaniline is replaced as open-chain crown ether, RS004 is prepared by the method for prepare compound RS001.1H NMR(DMSO,300MHz):δ 10.49 (s, 1H), 8.48 (d, J=1.8Hz, 1H), 7.16 (d, J=6.6Hz, 2H), 7.99 (d, J=8.7Hz, 1H), 7.44-7.41 (m, 2H), 7.23 (d, J=3.6Hz, 1H), 6.85 (d, J=3.6Hz, 1H), 6.78 (d, J =3.6Hz, 1H), 2.39 (s, 3H)
Embodiment 1-5,5- bromine furans -2- carboxylic acids [2- (3,5- 3,5-dimethylphenyl) -2H- benzotriazole -5- bases]-acid amides (RS005) preparation
P-nethoxyaniline is replaced as 3,5- dimethylanilines, RS005 is prepared by the method for prepare compound RS001.1H NMR(DMSO,300MHz):δ 8.48 (s, 1H), 8.16 (s, 1H), 7.96 (s, 2H), 7.91 (d, J=9.0Hz, 1H), 7.48 (dd, J=1.5,1.8Hz, 1H), 7.26-7.24 (m, 1H), 7.09 (s, 1H), 6.53 (d, J=3.3Hz, 1H), 2.44 (s,6H).
Embodiment 1-6,5- bromine furans -2- carboxylic acids [2- (4- benzyloxy-phenyls) -2H- benzotriazole -5- bases]-acid amides (RS006) preparation
P-nethoxyaniline is replaced as 4- benzyloxy-anilines, RS006 is prepared by the method for prepare compound RS001.1H NMR(DMSO,300MHz):δ 10.46 (s, 1H), 8.46 (d, J=1.2Hz, 1H), 8.19 (d, J=9.0Hz, 2H), 7.97 (d, J=9.0Hz, 1H), 7.73 (dd, J=1.8,1.8Hz, 1H), 7.49-7.22 (m, 8H), 6.85 (d, J=3.6Hz, 1H), 5.19(s,2H).
Embodiment 1-7,5- bromine furans -2- carboxylic acids [2- (4- acetylamino phenyls) -2H- benzotriazole -5- bases]-acid amides (RS007) preparation
P-nethoxyaniline is replaced as 4- acetylaminoanilines, RS007 is prepared by the method for prepare compound RS001.1H NMR(DMSO,300MHz):δ 10.51 (s, 1H), 10.30 (s, 1H), 8.48 (s, 1H), 8.21 (d, J=9.0Hz, 2H), 8.00-7.95 (m, 2H), 7.83 (dd, J=0.3,0.3Hz, 2H), 7.77-7.76 (m, 1H), 7.44 (d, J=3.3Hz, 1H), 6.86 (t, J=1.8Hz, 1H), 4.20-4.19 (m, 3H)
Embodiment 1-8,5- bromine furans -2- carboxylic acids [2- (4- cyano-phenyls) -2H- benzotriazole -5- bases]-acid amides (RS008) preparation
P-nethoxyaniline is replaced as 4- cyano-anilines, RS008 is prepared by the method for prepare compound RS001.1H NMR(DMSO,300MHz):δ 10.55 (s, 1H), 8.50 (s, 1H), 8.44 (dd, J=0.6,0.3Hz, 2H), 8.03-7.96 (m, 2H), 7.81-7.80 (m, 1H), 7.47-7.46 (m, 1H), 6.88 (d, J=1.8Hz, 1H)
Embodiment 1-9,5- bromine furans -2- carboxylic acids [2- (4- fluorophenyls) -2H- benzotriazole -5- bases]-acid amides (RS009) Preparation
P-nethoxyaniline is replaced as 4- fluoroanilines, RS009 is prepared by the method for prepare compound RS001.1H NMR (DMSO,300MHz):δ 10.51 (s, 1H), 8.51 (s, 1H), 8.33 (s, 2H), 8.02 (d, J=9.3Hz, 2H), 7.79- 7.76 (d, J=9.3Hz, 1H), 7.53-7.45 (m, 3H), 6.88 (s, 1H)
Embodiment 1-10,5- bromine furans -2- carboxylic acids [2- (3,4,5- trimethoxyphenyls) -2H- benzotriazole -5- bases] - The preparation of acid amides (RS010)
P-nethoxyaniline is replaced as 3,4,5- trimethoxy-anilines, is prepared by the method for prepare compound RS001 RS010。1H NMR(DMSO,300MHz):δ 10.53 (s, 1H), 8.51 (s, 1H), 8.01 (d, J=9.3Hz, 1H), 7.77 (s, 1H), 7.59 (s, 2H), 7.45 (d, J=3.6Hz, 1H), 6.89 (d, J=3.6Hz, 1H), 3.94 (s, 6H), 3.75 (s, 3H)
The preparation of embodiment 1-11,5- bromine furans -2- carboxylic acids [2- phenyl -2H- benzotriazole -5- bases]-acid amides (RS011)
P-nethoxyaniline is replaced as aniline, RS011 is prepared by the method for prepare compound RS001.1H NMR (DMSO,300MHz):δ 10.51 (s, 1H), 8.49 (s, 1H), 8.98 (dd, J=0.3,0.3Hz, 1H), 7.78 (t, J= 0.9Hz, 1H), 7.70-7.35 (m, 6H), 6.87 (d, J=3.3Hz, 1H)
The preparation of embodiment 1-12,5- bromine furans -2- carboxylic acids [2- benzyl -2H- benzotriazole -5- bases]-acid amides (RS012)
P-nethoxyaniline is replaced as benzylamine, RS012 is prepared by the method for prepare compound RS001.1H NMR (DMSO,300MHz):δ 10.41 (s, 1H), 8.37 (d, J=1.8Hz, 1H), 7.89 (d, J=9.0Hz, 1H), 7.67 (dd, J =1.81.5Hz, 1H), 7.40-7.30 (m, 6H), 6.84 (d, J=3.6Hz, 1H), 5.91 (s, 2H)
Embodiment 1-13,5- bromine furans -2- carboxylic acids [1- (3- phenyl propyls) -1H- benzotriazole -5- bases]-acid amides (RS013) preparation
P-nethoxyaniline is replaced as amphetamine, RS013 is prepared by the method for prepare compound RS001.1H NMR (DMSO,300MHz):δ 10.43 (s, 1H), 8.38 (t, J=0.9Hz, 1H), 7.89 (dd, J=0.6,0.6Hz, 1H), 7.67 (dd, J=2.1,1.8Hz, 1H), 7.40 (d, J=3.6Hz, 1H), 7.30-7.14 (m, 5H), 6.84 (d, J=3.6Hz, 1H), 4.68 (t, J=6.9Hz, 2H), 2.58 (t, J=7.5Hz, 2H), 2.34-2.29 (m, 2H)
Embodiment 1-14,1- phenyl carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides (RS014) Preparation
By 2- (4- methoxyphenyls) -5- amino -2H- benzotriazole (0.24g, 1.00mmol), benzoic acid (0.12g, 1.00mmol), HOBt (0.15g, 1.11mmol) and EDC.HCl (0.25g, 1.30mmol) are dissolved in DMF, at 50-60 DEG C It is stirred under oil bath, is detected with TLC, until the reaction is complete.Then excessive water is added, is carried out with ethyl acetate and water Extraction, merges organic phase, vacuum distillation, obtains crude product, (mobile phase is separated with column chromatography:Methylene chloride/methanol), it must produce Thing 1- phenyl carboxylic acids [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides (RS014,189mg, yield 55%).1H NMR(DMSO,300MHz):δ 10.41 (s, 1H), 8.20 (d, J=2.4Hz, 1H), 7.99 (dd, J=1.5,1.5Hz, 2H), 7.98-7.91(m,3H),7.80-7.70(m,1H),7.64-7.40(m,3H),7.19-7.16(m,2H),3.98(s,3H).
Embodiment 1-15,1- (2- pyridine radicals)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides (RS015) preparation
Benzoic acid is replaced as 2- pyridine carboxylic acids, RS015 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ10.96(s,1H),8.78-8.76(m,1H),8.67(s,1H),8.22-8.19(m,4H),8.12- 7.93 (m, 3H), 7.18 (dd, J=2.4,2.4Hz, 2H), 3.85 (s, 3H)
Embodiment 1-16,1- (2,3,4- trimethoxyphenyl)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole - 5- yls]-acid amides (RS016) preparation
Benzoic acid is replaced as 2,3,4-trimethoxybenzoic acid, RS016 is prepared by the method for prepare compound RS014.1H NMR(DMSO,300MHz):δ 10.40 (s, 1H), 8.5 (s, 1H), 8.20 (d, J=8.7Hz, 2H), 7.93 (d, J= 9.3Hz, 1H), 7.63 (s, 1H), 7.33 (d, J=8.7Hz, 1H), 7.17 (d, J=9.0Hz, 2H), 6.94 (d, J=9.0Hz, 1H),3.97(s,3H),3.85(s,3H),3.84(s,3H),3.79(s,3H).
Embodiment 1-17,1- (2,4- Dimethoxyphenyl)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- Base]-acid amides (RS017) preparation
Benzoic acid is replaced as 2,4- dimethoxybenzoic acids, RS017 is prepared by the method for prepare compound RS014.1H NMR(DMSO,300MHz):δ 10.56 (s, 1H), 8.59 (s, 1H), 8.23 (s, 2H), 7.98 (d, J=9.0Hz, 1H), 7.65 (d, J=9.3Hz, 1H), 7.22-7.17 (m, 5H), 3.86 (s, 9H)
Embodiment 1-18,2- (4- iodophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS018) preparation
Benzoic acid is replaced as 4- iodobenzene acetic acid, RS018 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.47 (s, 1H), 8.43 (d, J=1.2Hz, 1H), 8.19 (d, J=9.3Hz, 2H), 7.96 (d, J= 9.3Hz, 1H), 7.50 (dd, J=1.8,2.1Hz, 1H), 7.42-7.38 (m, 2H), 7.20-7.14 (m, 4H), 3.85 (s, 3H),3.73(s,2H).
Embodiment 1-19,2- (4- bromophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS019) preparation
Benzoic acid is replaced as 4- bromo-acids, RS019 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.47 (s, 1H), 8.42 (d, J=1.2Hz, 1H), 8.19 (d, J=9.3Hz, 2H), 7.95 (d, J= 9.3Hz, 1H), 7.53 (dd, J=1.8,2.1Hz, 1H), 7.40-7.36 (m, 2H), 7.20-7.14 (m, 4H), 3.87 (s, 3H),3.70(s,2H).
Embodiment 1-20,2- (4- chlorphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS020) preparation
Benzoic acid is replaced as 4- chlorobenzene acetic acids, RS020 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.47 (s, 1H), 8.43 (d, J=1.2Hz, 1H), 8.19 (d, J=9.3Hz, 2H), 7.96 (d, J= 9.3Hz, 1H), 7.54 (dd, J=1.8,2.1Hz, 1H), 7.41-7.36 (m, 2H), 7.20-7.14 (m, 4H), 3.86 (s, 3H),3.72(s,2H).
Embodiment 1-21,2- (4- fluorophenyls)-N- [2- (4- methoxyl groups-phenyl) -2H- benzotriazole -5- bases]-acetamide (RS021) preparation
Benzoic acid is replaced as 4- fluorophenylacetic acids, RS021 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.47 (s, 1H), 8.42 (d, J=0.9Hz, 1H), 8.19 (d, J=9.0Hz, 2H), 7.50 (d, J= 9.3Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.49 (dd, J=1.81.8,1H), 7.20-7.14 (m, 4H), 3.84 (s, 3H),3.69(s,2H).
Embodiment 1-22,2- (2- bromophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS022) preparation
Benzoic acid is replaced as 2- bromo-acids, RS022 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ10.56(s,1H),8.50-7.29(m,11H),3.95-3.85(m,5H).
Embodiment 1-23,2- (4- aminomethyl phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetyl The preparation of amine (RS023)
Benzoic acid is replaced as 4- methylphenyl acetic acids, RS023 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.43 (s, 1H), 8.42 (s, 1H), 8.17 (d, J=9Hz, 2H), 7.93 (d, J=9.3Hz, 1H), 7.48 (dd, J=1.5,1.5Hz, 1H), 7.24 (d, J=8.1Hz, 2H), 7.16-7.11 (m, J=15.3Hz, 4H), 3.83 (s,3H),3.64(s,2H),2.26(s,3H).
Embodiment 1-24,2- (4- sulfonyloxy methyls phenyl)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases] - The preparation of acetamide (RS024)
Benzoic acid is replaced as 4- sulfonyloxy methyl phenylacetic acids, RS024 is prepared by the method for prepare compound RS014.1H NMR(DMSO,300MHz):δ 10.56 (s, 1H), 8.42 (s, 1H), 8.17 (d, J=9Hz, 2H), 7.97-7.94 (m, J= 9.3Hz, 1H), 7.90 (d, J=5.4Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.48 (dd, J=1.51.5Hz, 1H), 7.16 (d, J=9.0Hz, 2H), 5.74 (s, 1H), 3.87 (s, 2H), 3.83 (s, 3H), 3.19 (s, 3H)
Embodiment 1-25,2- (4- nitrobenzophenones)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetyl The preparation of amine (RS025)
Benzoic acid is replaced as 4- nitrophenyl-acetic acids, RS025 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.58 (s, 1H), 8.41 (s, 1H), 8.19 (t, J=18.6Hz, 4H), 7.96 (d, J=9.3Hz, 1H), 7.64 (d, J=8.7Hz, 2H), 7.50-7.46 (m, 1H), 7.15 (d, J=9.3Hz, 2H), 3.91 (s, 2H), 3.83 (s,3H).
Embodiment 1-26,2- (4- methoxyphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-second The preparation of acid amides (RS026)
Benzoic acid is replaced as 4- methoxyphenylacetic acids, RS026 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.44 (s, 1H), 8.43 (s, 1H), 8.16 (d, J=9.0Hz, 2H), 7.93 (d, J=9.3Hz, 1H), 7.47 (dd, J=1.2,1.2Hz, 1H), 7.26 (d, J=8.4Hz, 2H), 7.14 (d, J=9.0Hz, 2H), 6.88 (d, J =8.7Hz, 2H), 3.82 (s, 3H), 3.71 (s, 3H), 3.62 (s, 2H)
Embodiment 1-27,2- (3,4,5- trimethoxyphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- Base]-acetamide (RS027) preparation
Benzoic acid is replaced as 3,4,5- trimethoxy phenyl acetic acids, RS027 is prepared by the method for prepare compound RS014.1H NMR(DMSO,300MHz):δ 10.42 (s, 1H), 9.27 (s, 1H), 8.43 (s, 1H), 8.18 (d, J=9.0Hz, 2H), 7.95-7.92 (m, 2H), 7.48 (dd, J=1.5,1.5Hz, 1H), 7.15 (d, J=9.3Hz, 2H), 6.67 (s, 1Hz), 3.83 (s,3H),3.76(s,6H),3.62(s,3Hz).
The bromo- N- of embodiment 1-28,4- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-butyramide (RS028) Prepare
Benzoic acid is replaced as 4- bromo-butyric acids, RS028 is prepared by the method for prepare compound RS014.1H NMR(DMSO, 300MHz):δ 10.26 (s, 1H), 8.43 (s, 1H), 8.18 (d, J=9.3Hz, 1H), 7.93 (d, J=9.0Hz, 2H), 7.46 (dd, J=1.5,1.5Hz, 1H), 7.16 (d, J=9.0Hz, 2H), 3.83 (s, 3H), 3.77 (t, J=12.9Hz, 2H), 2.57-2.48 (m, 2H), 2.06 (t, J=14.1Hz, 2H)
Embodiment 1-29,3- ((2- (4- methoxyphenyl -2H- benzotriazole -5- bases) amino) -3- Oxoacetic Acids (RS029) preparation
Benzoic acid is replaced as malonic acid, RS029 is prepared by the method for prepare compound RS014.1H NMR(DMSO, 300MHz):δ 10.54 (s, 1H), 8.47 (s, 1H), 8.17 (d, J=9.0Hz, 2H), 7.96 (d, J=9.0Hz, 1H), 7.51 (d, J=8.7Hz, 1H), 7.16 (d, J=8.7Hz, 2H), 3.84 (s, 3H), 3.63 (s, 1H), 3.32 (s, 2H)
The bromo- N- of embodiment 1-30,2- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS030) Prepare
Benzoic acid is replaced as monobromo-acetic acid, RS030 is prepared by the method for prepare compound RS014.1H NMR(DMSO, 300MHz):δ 10.61 (s, 1H), 8.43 (d, J=1.2Hz, 1H), 8.21 (d, J=9.0Hz, 2H), 7.98 (d, J=9.0Hz, 1H), 7.48 (dd, J=1.5,1.5Hz, 1H), 7.17 (d, J=9.3Hz, 1H), 4.34 (s, 2H), 3.85 (s, 3H)
The bromo- N- of embodiment 1-31,2- [2- (3,4,5- trimethoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS031) preparation
Benzoic acid is replaced as monobromo-acetic acid, 2- (4- methoxyphenyls) -5- amino -2H- benzotriazole is replaced into 2- (3,4,5- trimethoxyphenyl) -5- amino -2H- benzotriazole, RS031 is prepared by the method for prepare compound RS014 。1H NMR(DMSO,300MHz):δ 10.63 (s, 1H), 8.43 (s, 1H), 7.98 (d, J=9.0Hz, 1H), 7.55-7.48 (m, 3H),4.34(s,2H),3.92(s,6H),3.74(s,3H).
Embodiment 1-32,2- cyano group-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS032) Preparation
Benzoic acid is replaced as 2- cyanoacetic acids, RS032 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.60 (s, 1H), 8.37 (d, J=0.9Hz, 1H), 8.19 (dd, J=3.93.3Hz, 2H), 7.98 (d, J=9.0Hz, 1H), 7.44 (dd, J=1.8,1.8Hz, 1H), 7.19-7.16 (m, 2H), 3.99 (s, 2H), 3.86 (s, 3H).
Embodiment 1-33,2- methoxyl group-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS033) preparation
Benzoic acid is replaced as 2- methoxyacetic acids, RS033 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.06 (s, 1H), 8.46 (d, J=1.2Hz, 1H), 8.20 (d, J=9.0Hz, 2H), 7.95 (d, J= 9.3Hz, 1H), 7.65 (dd, J=1.8,1.8Hz, 1H), 7.17 (d, J=9.0Hz, 2H), 4.08 (s, 2H), 3.85 (s, 3H), 3.42(s,3H).
Embodiment 1-34,2- (2- methoxy ethyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-second The preparation of acid amides (RS034)
Benzoic acid is replaced as 2- (2- methoxy ethyls) Oxoacetic Acid, is prepared by the method for prepare compound RS014 RS034。1H NMR(DMSO,300MHz):δ 9.95 (s, 1H), 8.45 (s, 1H), 8.20 (d, J=9.0Hz, 2H), 7.96 (d, J =9.3Hz, 1H), 7.57 (dd, J=1.5,1.5Hz, 1H), 7.16 (d, J=9.3Hz, 2H), 4.15 (s, 2H), 3.85 (s, 3H),3.73-3.70(m,2H),3.57-3.54(m,2H).
Embodiment 1-35,2- hydroxy-n-[2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS035) Preparation
Benzoic acid is replaced as 2- hydroxyacetic acids, RS035 is prepared by the method for prepare compound RS014.1H NMR (500MHz,DMSO):δ 10.01 (s, 1H), 8.50 (s, 1H), 8.21 (d, J=9.0Hz, 2H), 7.97 (dd, J=18.3, 8.8Hz, 2H), 7.72 (t, J=7.2Hz, 2H), 7.55 (t, J=7.6Hz, 1H), 7.42 (t, J=7.6Hz, 1H), 7.19 (d, J=9.1Hz, 2H), 4.08 (s, 2H), 3.86 (s, 3H)
Embodiment 1-36,1- cyclopropyl-carboxylic acid-[2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides (RS036) preparation
Benzoic acid is replaced as cyclopropaneacetic acid, RS036 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.47 (s, 1H), 8.40 (d, J=0.9Hz, 1H), 8.15 (dd, J=2.1,2.1Hz, 2H), 7.92 (d, J=9.9Hz, 1H), 7.48 (dd, J=2.12.1Hz, 1H), 7.15 (dd, J=2.4,2.4Hz, 2H), 3.84 (s, 3H), 1.82(s,1H),0.85-0.80(m,4H).
Embodiment 1-37,2- (4- benzyloxy-phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-second The preparation of acid amides (RS037)
Benzoic acid is replaced as 4- benzyloxy phenylacetic acids, RS037 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.43 (s, 1H), 9.27 (s, 1H), 8.43 (s, 1H), 8.18 (d, J=9.0Hz, 1H), 7.93 (d, J =9.0Hz, 1H), 7.49-7.25 (m, 8H), 7.14 (d, J=9.0Hz, 2H), 6.98 (d, J=8.7Hz, 2H), 5.06 (s, 2H),3.82(s,3H),3.62(s,2H).
Embodiment 1-38,2- (4- hydroxy phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetyl The preparation of amine (RS038)
Benzoic acid is replaced as 4- hydroxyl phenylacetic acids, RS038 is prepared by the method for prepare compound RS014.1H NMR (DMSO,300MHz):δ 10.40 (s, 1H), 9.27 (s, 1H), 8.44 (s, 1H), 8.21 (d, J=9.0Hz, 1H), 7.96 (d, J =9.0Hz, 1H), 7.50 (dd, J=1.51.5Hz, 1H), 7.19-7.14 (m, 4H), 6.73 (d, J=8.4Hz, 2H), 3.86 (s,3H),3.58(s,2H).
Embodiment 1-39,2- (4- isopropyl phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases] - The preparation of acetamide (RS039)
Benzoic acid is replaced as 4- isopropoxy phenylacetic acids, RS039 is prepared by the method for prepare compound RS014.1H NMR(DMSO,300MHz):δ 10.41 (s, 1H), 8.43 (s, 1H), 8.18 (d, J=9.3Hz, 1H), 7.94 (d, J=9.0Hz, 1H), 7.48 (dd, J=1.5,1.5Hz, 1H), 7.24 (d, J=8.4Hz, 2H), 7.16 (d, J=9.0Hz, 2H), 6.86 (d, J =8.4Hz, 2H), 4.77-4.73 (m, 1H), 3.83 (s, 3H), 3.6 (s, 2H), 1.22 (d, J=6Hz, 6H)
Embodiment 1-40,2- (4- propoxyphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-second The preparation of acid amides (RS040)
Benzoic acid is replaced as 4- positive propoxy phenylacetic acids, RS040 is prepared by the method for prepare compound RS014.1H NMR(DMSO,300MHz):δ 10.42 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=9.3Hz, 2H), 7.97-7.94 (m, 1H), 7.50 (dd, J=1.5,1.5Hz, 1H), 7.27 (d, J=8.7Hz, 2H), 7.18 (d, J=9.0Hz, 2H), 6.90 (d, J= 8.7Hz, 2H), 3.90 (t, J=13.2Hz, 2H), 3.85 (s, 3H), 3.63 (s, 2H), 1.75-1.68 (m, 2H), 0.99- 0.94(m,3H).
Embodiment 1-41,2- (4- cyclopentyloxies phenyl)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases] - The preparation of acetamide (RS041)
Benzoic acid is replaced as 4- cyclopentyloxy phenylacetic acids, RS041 is prepared by the method for prepare compound RS014.1H NMR(DMSO,300MHz):δ 10.43 (s, 1H), 8.43 (s, 1H), 8.18 (d, J=9.3Hz, 1H), 7.94 (d, J=9.0Hz, 1H), 7.48 (dd, J=1.5,1.5Hz, 1H), 7.23 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 6.84 (d, J =8.7Hz, 2H), 4.75 (s, 1H), 3.83 (s, 3H), 3.6 (s, 2H)
Embodiment 1-42,5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls) -2H- benzotriazole (RS042) Prepare
By 2- (4- methoxyphenyls) -5- amino -2H- benzotriazole (0.42g, 1.74mmol), phenylacetic acid (0.24g, 1.74mmol), HOBt (0.26g, 1.92mmol) and EDC.HCl (0.43g, 2.24mmol) is dissolved in DMF (10ml), It is stirred under 50-60 DEG C of oil bath, is detected with TLC, until the reaction is complete.Excessive water is added, with ethyl acetate and water Extracted, merge organic phase, vacuum distillation, obtains crude product, separated with column chromatography, obtain pure N- (2- (4- methoxyl groups Phenyl) -2H- benzotriazole -5- amino) -2- phenyl-acetamides 0.57g, yield 91%.Then by N- (2- (4- methoxybenzenes Base) -2H- benzotriazole -5- amino) -2- phenyl-acetamides (0.57g, 1.59mmol) under condition of ice bath under be dissolved in THF In (10ml), lithium aluminium hydride reduction (0.60g, 15mmol) is added portionwise, when being produced to no bubble, removes ice bath, it is enterprising in oil bath Row reflux, TLC are detected until the reaction is complete.Excessive ethyl acetate is added, is extracted with ethyl acetate and water, is merged Organic phase, vacuum distillation, obtains crude product, is separated with column chromatography, obtain pure 5- (N-2- phenylethylcarbamates) -2- (4- Methoxyphenyl) -2H- benzotriazole 0.32g, yield 59%.1H NMR(DMSO,300MHz):δ 8.13 (d, J=9.0Hz, 2H), 7.69 (d, J=9.0Hz, 1H), 7.32 (s, 3H), 7.23-7.22 (m, 1H), 7.13 (m, 2H), 7.03 (dd, J=0.3, 0.3Hz,1H),6.61(s,1H),6.33-6.32(m,1H),3.83(s,3H),3.62-3.36(m,2H),2.96-2.92(m, 2H).
Embodiment 1-43,5- (N-3- Phenylpropylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole (RS043) Prepare
Phenylacetic acid is replaced as benzenpropanoic acid, RS043 is prepared by the method for prepare compound RS042.1H NMR(DMSO, 300MHz):δ 8.08 (d, J=8.7Hz, 2H), 7.66 (d, J=9.3Hz, 1H), 7.29-6.99 (m, 8H), 6.47 (s, 1H), 6.26 (t, J=4.8Hz, 1H), 3.80 (s, 3H), 3.09-3.03 (m, 2H), 2.70 (t, J=8.4Hz, 2H), 1.96-1.88 (m,2H).
Embodiment 1-44,5- (N-4- methoxYbenzylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole (RS044) Preparation
Phenylacetic acid is replaced as 4- methoxy benzoic acids, RS044 is prepared by the method for prepare compound RS042.1H NMR (DMSO,300MHz):δ 8.08 (d, J=9.0Hz, 2H), 7.68 (dd, J=0.3,0.3Hz, 1H), 7.35 (d, J=9.3Hz, 2H), 7.15-7.12 (m, 3H), 6.93 (s, 1H), 6.91 (s, 1H), 6.80-6.76 (m, 1H), 4.27 (t, J=2.7Hz, 2H),3.84(s,3H),3.74(s,3H).
Embodiment 1-45,5- (N-2- methoxYbenzylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole (RS045) Preparation
Phenylacetic acid is replaced as O-Anisic Acid, RS045 is prepared by the method for prepare compound RS042.1H NMR (DMSO,300MHz):δ 8.06 (d, J=8.7Hz, 2H), 7.67 (d, J=9.0Hz, 1H), 7.27-7.22 (m, 1H), 7.13- 7.05 (m, 5H), 6.83-6.79 (m, 2H), 6.45 (d, J=1.8Hz, 1H), 4.32-4.30 (m, 2H), 3.81 (s, 3H), 3.72(s,3H).
Embodiment 1-46,5- (N-2- (4- methoxyphenyl ethyls) amino) -2- (4- methoxyphenyls) -2H- benzos three The preparation of azoles (RS046)
Phenylacetic acid is replaced as 4- methoxyphenylacetic acids, RS046 is prepared by the method for prepare compound RS042.1H NMR (DMSO,300MHz):δ 8.08 (d, J=9.0Hz, 2H), 7.65 (d, J=9.3Hz, 1H), 7.21 (d, J=8.1Hz, 2H), 7.11 (d, J=8.7Hz, 2H), 6.98 (d, J=3Hz, 1H), 6.85 (d, J=8.1Hz, 2H), 6.56 (s, 1H), 6.27 (t, J =5.1Hz, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.30-3.23 (m, 2H), 3.84 (t, J=7.2Hz), 2.06 (s, 3H).
Embodiment 1-47,5- (N-2,4- Dimethoxybenzylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole (RS047) preparation
Phenylacetic acid is replaced as 2,4- dimethoxybenzoic acids, RS047 is prepared by the method for prepare compound RS042.1H NMR(DMSO,300MHz):δ 8.08 (d, J=9.0Hz, 2H), 7.68 (d, J=9.3Hz, 1H), 7.13-6.93 (m, 6H), 6.69 (s, 1H), 6.47 (s, 1H), 4.34 (d, J=5.4Hz, 2H), 3.82 (d, J=3.6Hz, 9H)
Embodiment 1-48,5- (N-2,4,6- trimethoxy benzyls amino) -2- (4- methoxyphenyls) -2H- benzotriazole (RS048) preparation
Phenylacetic acid is replaced as 2,4,6- trimethoxybenzoic acids, RS048 is prepared by the method for prepare compound RS042.1H NMR(DMSO,300MHz):δ 8.09 (d, J=9.0Hz, 2H), 7.58 (d, J=9.0Hz, 1H), 7.11 (d, J=9.0Hz, 2H), 7.02 (dd, J=1.81.8Hz, 1H), 6.60 (s, 2H), 6.25 (s, 2H), 5.95-5.92 (m, 1H), 4.08 (d, J= 4.8Hz,2H),3.82(s,3H),3.79(s,3H),3.76(s,3H).
Embodiment 1-49,5- (N-4- trifluoromethyl benzyls amino) -2- (4- methoxyphenyls) -2H- benzotriazole (RS049) preparation
Phenylacetic acid is replaced as 4- trifluoromethylbenzoic acids, RS049 is prepared by the method for prepare compound RS042.1H NMR(DMSO,300MHz):δ8.06-8.03(m,2H),7.71-7.60(m,5H),7.11-6.96(m,4H),6.42-6.41 (m,1H),4.47-4.45(m,2H),3.80(s,3H).
The system of embodiment 1-50,5- (N-3- bromobenzyls amino) -2- (4- methoxyphenyls) -2H- benzotriazole (RS050) It is standby
Phenylacetic acid is replaced as 3- bromobenzoic acids, RS050 is prepared by the method for prepare compound RS042.1H NMR (DMSO,300MHz):δ 8.07 (s, J=9.0Hz, 2H), 7.70 (d, J=8.7Hz, 1H), 7.62 (s, 1H), 7.45-7.28 (m, 3H), 7.13-7.07 (m, 2H), 6.91-6.87 (m, 1H), 6.48 (s, 1H), 4.38 (d, J=0.6Hz, 2H), 3.83 (s, 3H).
Embodiment 1-51,5- (N-2- (3,4,5- trimethoxyphenyls) ethylamino) -2- (4- methoxyphenyls) -2H- The preparation of benzotriazole (RS051)
Phenylacetic acid is replaced as 3,4,5- trimethoxy phenyl acetic acids, RS051 is prepared by the method for prepare compound RS042.1H NMR(DMSO,300MHz):δ 8.11 (d, J=9.0Hz, 2H), 7.69 (d, J=9.3Hz, 1H), 7.14 (d, J=9.3Hz, 2H), 7.03 (dd, J=1.81.8Hz, 1H), 6.63 (s, 3H), 6.32-6.28 (m, 1H), 3.38 (s, 2H), 3.78 (s, 9H), 2.87-2.86(m,2H).
Embodiment 1-52,5- (N- (2- furfuryls) amino) -2- (4- methoxyphenyls) -2H- benzotriazole (RS052) Preparation
Phenylacetic acid is replaced as 2- furancarboxylic acids, RS052 is prepared by the method for prepare compound RS042.1H NMR (DMSO,300MHz):δ 8.10 (d, J=8.7Hz, 2H), 7.68 (d, J=9.3Hz, 1H), 7.60 (s, 1H), 7.13 (d, J= 8.7Hz, 2H), 7.05 (d, J=9.0Hz, 1H), 6.67 (s, 2H), 6.41 (s, 1H), 4.33 (d, J=5.4Hz, 2H) 3.83 (s,3H).
The chloro- N- of embodiment 1-53,1- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS053) Prepare
By 2- (4- methoxyphenyls) -5- amino -2H- benzotriazole (0.16g, 0.67mmol) and triethylamine (0.5ml) is dissolved in dichloromethane (10ml), and the chloracetyl chloride (0.2ml) being added dropwise under condition of ice bath, is detected with TLC Until the reaction is complete.Vacuum distillation removes solvent, is extracted with water and ethyl acetate, merges organic phase, and vacuum distillation obtains Crude product, with column chromatography carry out the isolated pure chloro- N- of product 1- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases] - Acetamide (0.17g, yield 75%).1H NMR(DMSO,300MHz):δ 10.62 (s, 1H), 8.43 (s, 1H), 8.20 (d, J= 8.7Hz, 2H), 7.99-7.96 (m, 1H), 7.48 (dd, J=1.51.5Hz, 1H), 7.17 (d, J=8.7Hz, 2H), 4.34 (s, 2H),3.85(s,3H).
The chloro- N- of embodiment 1-54,3- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-butyramide (RS054) Prepare
Chloracetyl chloride is replaced as 3- chlorpromazine chlorides, RS054 is prepared by the method for prepare compound RS053.1H NMR (DMSO,300MHz):δ 10.27 (s, 1H), 8.44 (s, 1H), 8.18 (d, J=9.0Hz, 2H), 7.94 (d, J=9.3Hz, 1H), 7.47 (dd, J=1.8,1.8Hz, 1H), 7.17 (d, J=9Hz, 2H), 3.85 (s, 3H), 3.73 (t, J=6.4Hz, 2H),2.59-2.50(m,2H),2.13-2.01(m,2H).
Embodiment 1-55,3- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases carbamoyl]-acrylic acid (RS055) preparation
Chloracetyl chloride is replaced as maleic anhydride, RS055 is prepared by the method for prepare compound RS053.1H NMR (DMSO,300MHz):δ 10.44 (s, 1H), 8.56 (s, 1H), 8.20 (d, J=9.0Hz, 2H), 7.97 (d, J=9.0Hz, 1H), 7.53 (dd, J=1.51.5Hz, 1H), 7.17 (d, J=9.0Hz, 2H), 6.55-6.30 (m, 2H), 5.82 (dd, J= 1.51.8Hz,1H),3.85(s,3H).
Embodiment 1-56, trifluoromethyl-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (RS056) preparation
Chloracetyl chloride is replaced as trifluoromethyl chloroacetic chloride, RS056 is prepared by the method for prepare compound RS053.1H NMR(DMSO,300MHz):δ 11.52 (s, 1H), 8.40 (s, 1H), 8.21 (t, J=7.5Hz, 2H), 8.04 (d, J=8.7Hz, 1H), 7.70 (d, J=9.0Hz, 1H), 7.17 (t, J=7.8Hz, 2H), 3.86 (s, 3H)
Embodiment 1-57, nitric acid 2- ((2- (4- methoxyphenyls) -2H- benzotriazole -5- bases) amino -2- oxoethyls The preparation of ester (RS057)
The bromo- N- of 2- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide (0.18g, 0.50mmol) is molten Solution adds silver nitrate (0.23g, 1.35mmol), is stirred, until the reaction is complete in acetone (10ml).It is evaporated under reduced pressure acetone, Extracted with water and ethyl acetate, merge organic phase, vacuum distillation, obtains crude product, separated through column chromatography, obtained pure Product 0.16g, yield 96%.1H NMR(DMSO,300MHz):δ 10.60 (s, 1H), 8.41 (d, J=9.0Hz, 1H), 8.20 (d, J=9.3Hz, 2H), 7.97 (d, J=9.0Hz, 1H), 7.47 (dd, J=1.51.5Hz, 1H), 7.17 (d, J=9Hz, 2H),4.32(s,2H),3.84(s,3H).
Embodiment two：The inhibitory action that the compounds of this invention breeds RAS mutant cells
The compounds of this invention is first in T29 cell lines (RAS wild types) and T29KT1P cell lines (RAS saltant types) Carry out activity rating.This two plants of cells are specifically described as：SV40 viruses are transferred in primary chrotoplast on people's ovary top layer Early stage section obtain IOSE-29 cell lines, which reaches big T and small T antigens, can suppress p53 and PRb signal paths simultaneously extend the cell cycle, and IOSE-29 can be made to remain the exhausted most of normal epithelium cell in the 10th generation Number characteristic.Then, the T29 immortalized using the retroviral infection IOSE-29 cells comprising total length hTERT cDNA Cell line, while infect again comprising pBabe-puro-KRASV12Virus obtain T29KT1P cells.Both retrovirus Structure be to be transferred to respectively in amphitropic Retronituse encapsulated cell line Phoenix cells using calcium phosphate transfection method PBabe-hygro-hTERT or pBabe-puro-KRASV12Plasmid obtain, then collect viral supernatants, infect IOSE- respectively 29 cells obtain corresponding cell line.The metainfective cell line of virus, by hygromycin (100 mcg/mls, 7 days) and purine Mycin (0.5 mcg/ml, 5 days) is screened, and obtains stablizing the immortalization normal epithelium cell (T29) of expression and high table Up to KRAS albumen (T29KT1P) epithelial cell, wherein carrying KRASV12The T29KT1P cells of plasmid have cancer cell characteristics, can In mouse subcutaneously into knurl.The culture medium cultivated used in cell is by MCDB105 and M199 culture mediums 1:10% is added after 1 mixing The hyclone of inactivation, 1% green grass or young crops/streptomysin, cell are placed in 37 DEG C and contain 5%CO2, in 95% saturation of the air humidity constant temperature incubator Cultivated.
Statistical analysis：
Except specified otherwise is done, all results are represented with mean+SD (mean ± SD).Using Microsoft Excel or GraphPad Prism Software version 5.0. softwares carry out statistical test.Comparison between two samples Using " non-paired Student ' the s T of double tails are examined；Comparison between multisample uses one-way analysis of variance (One-way ANOVA).Significant difference represents with P values, P<0.05 thinks there is significant difference, P between group<0.05 (*), P<0.01 (* *), P<0.001(***).Other special statistical analysis refer to relevant portion explanation.
The method of this paper screening compounds is 5- [3- (Carboxvmethoxv) phenyl] -3- (4,5- dimethyl -2- thiazoles Base) -2- (4- sulfo groups phenyl) -2H- tetrazolium, inner salts (MTS) experimental method：T29 and T29KT1P cells are taped against 96 hole cell trainings Support on plate, the cell number in each hole is 4000, when cell attachment 24 is small after, it is different with different compounds and same compound Concentration handles two kinds of cells, and 48 add the survival rate of MTS measure cells afterwards when small.
Comparative survival rate of cells is as shown in table 2：
Proliferation Ability result of 2 the compounds of this invention of table (RS001-RS057) to T29KT1P and T29 cells
By result in table 2 it can be found that the inhibition of the T29 cell lines relative to RAS wild types, target compound The T29KT1P cells that RS001-RS057 is mutated RAS all have very excellent activity and selectivity (table 2 and Fig. 1), and RAS dashes forward Become the half inhibiting rate concentration of T29KT1P as 3 micromoles per liters, the half inhibiting rate concentration of RAS wild types T29 be 23 micromoles/ Rise.Illustrate the ability that there is this kind of compound specificity to suppress RAS mutant cell proliferation activities.
Embodiment three：Inhibition test of the compounds of this invention to the K-RAS tumor cell proliferations being mutated
To investigate the compounds of this invention to the inhibition of K-RAS mutated tumor cell Proliferations, we have chosen K-RAS and dash forward The lung carcinoma cell of change, colon-cancer cell, pancreatic cancer cell, breast cancer cell, uterine cancer cells, multiple cancer cell of bone marrow, stomach cancer Cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, prostate gland cancer cell, cervical cancer cell, neuroglial cytoma and K-RAS are wild The tumour cell (including the lung carcinoma cell of K-RAS wild types and colon cancer cell etc.) (table 3) of type and the suppression work to compound Property is tested.Basic test process is as follows：Take the logarithm growth period cell inoculation in 96 orifice plates, per hole access 100 microlitres Suspension containing 2,000-5,000 cells, after cell attachment and when small (24 after) add different medicines when being in exponential phase Thing processing, each concentration set 4-6 multiple holes；After when drug effect 48 is small, using CellTiter AQueous One Solution cell proliferation detecting kits (MTS) carry out the detection of cell survival rate, 20 microlitres of MTS reagents of addition per hole, and 37 DEG C be incubated 1-2 it is small when after, the light absorption value in each hole is detected under 490 nano wave length of microplate reader.Using cellular control unit survival rate as 100%, other each group light absorption values calculate corresponding survival rate compared with control group light absorption value.
Selected K-RAS mutated tumors cell line and K-RAS wild type tumor cell lines are as shown in table 3 in experiment：
3 K-RAS mutated tumors cell line of table and K-RAS wild type tumor cell lines
By Fig. 2 it turns out that, the compounds of this invention RS001-RS003, RS009-RS012, RS018, RS019, RS024, RS026, RS029-RS031, RS038, RS048, RS051-RS057 etc. significantly suppress K-RAS under 10 micromoles per liter concentration Tumour cell (lung carcinoma cell, colon-cancer cell, pancreatic cancer cell, breast cancer cell, uterine cancer cells, the multiple marrow of mutation Cancer cell, stomach cancer cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, prostate gland cancer cell, cervical cancer cell and glioma are thin Born of the same parents) proliferation activity, and obvious selectivity, difference are showed compared with the inhibitory activity of K-RAS wild type tumor cells With conspicuousness.Better choice is shown under 5 micromoles per liter concentration, the compounds of this invention group swells K-RAS mutation Oncocyte (lung carcinoma cell, colon-cancer cell, pancreatic cancer cell, breast cancer cell, uterine cancer cells, multiple cancer cell of bone marrow, stomach Cancer cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, prostate gland cancer cell, cervical cancer cell and neuroglial cytoma) opposite suppression Rate processed is all more than 50%, and to the inhibiting rates of K-RAS wild type tumor cells 20% or so.Other Compound RS 004- RS008, RS013-RS017, RS020-RS023, RS025, RS027, RS028, RS032-RS037, RS039-RS047 and The tumour cell that RS049-RS050 is mutated K-RAS include lung carcinoma cell, colon-cancer cell, pancreatic cancer cell, breast cancer cell, Uterine cancer cells, multiple cancer cell of bone marrow, stomach cancer cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, prostate gland cancer cell, uterine neck The Proliferation Ability of cancer cell and neuroglial cytoma also all shows similar inhibition.
Example IV：Inhibitory action of the compounds of this invention to RAS mutated tumor cell clonal formations
The detection of cell survival rate merely illustrates the number of short-term attached cell, but adherent cell cannot be guaranteed it is each It is a to have the ability for continuing to breed and being formed clone；And the cell that can form clone is necessary for adherent and with proliferation activity Cell, therefore, cloning efficiency can more reflect the multiplication capacity and colony's dependence of tumour cell continued propagation.In order to investigate Whether the compounds of this invention has irreversible growth inhibition effect to RAS mutated tumors cell, we dash forward using A549 RAS Become cell to study inhibitory action of the drug regimen to cell 2D and 3D Clone formation.The process of 2D colony formations is：Take The A549 cells of exponential phase, are digested with pancreatin and blow and beat into individual cells, and the density by every 800-1000 cell in hole is equal It is even to be inoculated in 6 orifice plates, after cell attachment, the drug-treated of various concentrations is added, fresh culture was replaced once per 2-3 days Base and medicine, put 37 DEG C, 5% CO2And cultivated one week in the environment of saturated humidity, it can be observed to occur in 6 orifice plates visually visible Clone, abandoning supernatant, is carefully embathed 2 times with PBS.The paraformaldehyde for adding 4% fixes 15 minutes.Then fixer is removed, Add appropriate 0.1% violet staining 10~30 minutes, then slowly wash away dyeing liquor with flowing water, be air-dried.Count and contain 50 Clone more than cell, calculates cell colony formation rate.The process of 3D (soft agarose) colony formation is：It is low by 1.2% Melt agarose and 2 × cell culture medium are with 1:1 volume ratio is mixed with 0.6% bottom-layer agar, each hole in 6 orifice plates 1.4 milliliters of greenhouse solidifications, phase cell of taking the logarithm, dispels into individual cells suspension after Trypsin Induced, count, and diluting cells Suspension to concentration is 10000/milliliter, by 0.7% low melting-point agarose and 2 × cell culture medium with 1:1 volume ratio mixing, 0.35% top-layer agar is prepared, adds 1 milliliter of top-layer agar and 100 microlitres of single cell suspensions (about 1000 cell per well) per hole, Mix, room temperature solidification.37 DEG C are placed in, 5% CO2Cell incubator in cultivate 2-3 weeks, count containing it is more than 50 cells gram It is grand, calculate cell colony formation rate.Take pictures under the microscope at the same time, amplification factor for 40 ×.
Experimental result as shown in figure 3, the compounds of this invention RS001-RS006, RS009-RS015, RS018-RS022, RS024-RS027, RS029-RS031, RS033-RS048, RS051-RS057 can not only significantly inhibit the size of Clone formation, It may also suppress the number of Clone formation.Verified through follow-up test, tumour such as intestinal cancer that the compounds of this invention is mutated in other RAS, Cancer of pancreas, breast cancer, uterine cancer, multiple bone marrow cancer, stomach cancer, oophoroma, carcinoma of urinary bladder, prostate cancer, cervical carcinoma and neuroglia The size and number of the isocellular Clone formation of matter knurl have obvious inhibition.
Embodiment five：Histamine result of the compounds of this invention to RAS mutation entity tumors
For investigate the compounds of this invention to RAS be mutated entity tumor inhibition, we have chosen RS002, RS018, RS019, RS024, RS026, RS030, RS038, RS048, RS053 and RS057, investigate their suppressions to the RAS tumours being mutated Effect processed.Basic experiment process is as follows：A549 cells (5 × 10 in exponential phase6) use collected by trypsinisation, 1 × PBS Wash twice, be resuspended with the RPMI-1640 culture mediums of 0.1 milliliter of serum-free, be expelled to 5-6 weeks BALB/cA right flank of athymic nude mice Dorsal sc, establishes nude mice by subcutaneous lotus knurl model, after entity tumor rises to 150~200 cubic millimeters or so, average packet (n=8~10) are administered；Every two days mice with tumor weight of record and with vernier caliper measurement solid tumor size size, tumour body Accumulating calculation formula is：Volume=length × wide2×0.52.Mice with tumor is put to death after being administered 4 weeks, entity tumor is peeled off, takes pictures and weigh.
The results are shown in Figure 4, and the compounds of this invention is under the dosage of 1 mg/kg, 2 mg/kgs and 4 mg/kgs The growth of tumour can be significantly inhibited, the compounds of this invention group has the significance difference opposite sex compared with control group.After administration 30 days, Gross tumor volume is narrowed down to about 900,800 and 500 cubic millimeters or so (Fig. 4) respectively by about 1800 cubic millimeters of control group；Stripping From tumor weight be decreased to 1.2 grams, 1.0 grams and 0.8 gram or so respectively by 1.5 grams of control group or so, illustrate the present inventionization Compound can significantly suppress the growth of the tumour of RAS mutation, and be in dose-dependent relation.Also confirmed that through follow-up test, this Invention Compound RS 001-RS057 is in intestinal cancer, cancer of pancreas, breast cancer, uterine cancer, multiple bone marrow cancer, stomach cancer, oophoroma, wing Guang cancer, prostate cancer, cervical carcinoma and glioma growth on also show the inhibition similar in lung cancer.
Embodiment six：Inhibitory action of the compounds of this invention to RAS genetically modified animal Model Tumors
In order to further investigate inhibition of the compounds of this invention to the RAS mutated tumors in body, we apply Lox- STOP-Lox-KRASG12DGenetically modified animal model, investigate RS002, RS018, RS019, RS024, RS026, RS030, The inhibition for the primary tumo(u)r that RS038, RS048, RS053 and RS057 induce KRAS mutation.Basic experiment process is as follows： By in Lox-STOP-Lox-KRASG12DCre enzymes are introduced in mouse nasal cavity, are led in the expression of lung fixed point Mutation induction RAS Oncogenic generation.When lung tumors are in progress two months or so (the obvious tubercle of section Observable), average packet administration.Give After medicine four weeks, imaged through Micro-CT, observe the growing state of each group lung tumors.
As shown in figure 5, the compounds of this invention RS002, RS018, RS019, RS024, RS026, RS030, RS038, RS048, RS053 and RS057 can significantly inhibit the progress of lung tumors in 2 mg/kgs, 4 mg/kgs, with control group Compare, the compounds of this invention RS002, RS018, RS019, RS024, RS026, RS030, RS038, RS048, RS053 and RS057 63% is up to the inhibiting rate of gross tumor volume with the administration group of 2 mg/kgs, the compounds of this invention RS002, RS018, RS019, RS024, RS026, RS030, RS038, RS048, RS053 and RS057 are with the administration group of 4 mg/kgs to tumour body Long-pending inhibiting rate is up to 75%.In addition, verified through follow-up test, the tumour such as intestines that the compounds of this invention is mutated in other RAS Cancer, cancer of pancreas, breast cancer, uterine cancer, multiple bone marrow cancer, stomach cancer, oophoroma, carcinoma of urinary bladder, prostate cancer, cervical carcinoma and nerve Significant therapeutic effect is all shown in glioma.
The protection content of the present invention is not limited to above example.Without departing from the spirit and scope of the invention, originally Field technology personnel it is conceivable that change and advantage be all included in the present invention, and using appended claims as protect Protect scope.

Claims (12)

1. a kind of benzotriazole compound or its pharmaceutically acceptable salt, it is characterised in that it is by following structural formula (I) Represent：
Wherein：
M and p refers to the number of chain methylene, m=0,1,2,3 or 4；P=0,1,2,3 or 4；
N refers to the number of carbonyl, n=0 or 1；
R1Refer to the substituent on phenyl ring, be derived from one or more of following groups, be hydrogen, methyl, methoxyl group, halogen, benzyloxy Base, cyano group, amide groups；
R2For cyano group, ONO2, halogen, hydroxyl, carboxyl, methoxyl group, cyclopropane base, furyl, vinyl, vinyl carboxyl, trifluoro Methyl, 5- bromines furyl, phenyl, pyridine radicals, tolyl, methylsulfonyl phenyl, C1-C3 alkoxyl phenyls, cyclopentyloxy phenyl, halogen For phenyl, nitrobenzophenone, benzyloxy-phenyl or hydroxy phenyl；
Wherein, m=0, n=1, p=0, R are worked as2For furyl, 5- bromines furyl or pyridine radicals when, R1Not equal in following groups One or more, fluorine, chlorine, bromine, hydrogen, methyl, methoxyl group；
Work as m=0, n=1, p=0, R1For amide groups when, R2Not equal to phenyl, benzyloxy-phenyl, nitrobenzophenone, ethoxyl phenenyl, Tolyl, iodine substituted phenyl, bromo phenyl；
Work as m=0, n=0, p=1, R2For pyridine radicals when, R1Not equal to one or more methoxyl groups.
2. a kind of benzotriazole compound or its pharmaceutically acceptable salt, it is characterised in that it is by following structural formula (II) represent：
Wherein：
P refers to the number of chain methylene, p=0,1,2,3 or 4；
N refers to the number of carbonyl, n=0 or 1；
R1Refer to the substituent on phenyl ring, be derived from one or more of following groups, be hydrogen, methyl, methoxyl group, halogen, benzyloxy Base, cyano group, amide groups；
R3For hydrogen, hydroxyl, methyl, halogen, C1-C3 alkoxies, cyclopentyloxy, trifluoromethyl, benzyloxy, nitro or mesyl In one；
Wherein, n=1, p=0, R are worked as1For amide groups when, R3Not equal in hydrogen, Bian epoxide, nitro, ethyoxyl, methyl, iodine, chlorine One.
3. a kind of benzotriazole compound or its pharmaceutically acceptable salt, it is characterised in that including：
5- bromine furans -2- carboxylic acids [2- (3,5- 3,5-dimethylphenyl) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- benzyloxy-phenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- acetylamino phenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (4- cyano-phenyls) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- (3,4,5- trimethoxyphenyl) -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [2- benzyl -2H- benzotriazole -5- bases]-acid amides,
5- bromine furans -2- carboxylic acids [1- (3- phenyl propyls) -1H- benzotriazole -5- bases]-acid amides,
1- phenyl carboxylic acids [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
1- (2- pyridine radicals)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
1- (2,3,4- trimethoxyphenyl)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
1- (2,4- Dimethoxyphenyl)-carboxylic acid [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
2- (4- iodophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- bromophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- chlorphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- fluoro-phenyls)-N- [2- (4- methoxyl groups-phenyl) -2H- benzotriazole -5- bases]-acetamide,
2- (2- bromophenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- aminomethyl phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- sulfonyloxy methyls phenyl)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- nitrobenzophenones)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- methoxyphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (3,4,5- trimethoxyphenyl)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
The bromo- N- of 4- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-butyramide,
3- (2- (4- methoxyphenyl -2H- benzotriazole -5- bases) amino) -3- Oxoacetic Acids,
The bromo- N- of 2- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
The bromo- N- of 2- [2- (3,4,5- trimethoxyphenyl) -2H- benzotriazole -5- bases]-acetamide,
2- cyano group-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- methoxyl groups-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (2- methoxy ethyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- hydroxy-ns-[2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
1- cyclopropyl-carboxylic acids-[2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acid amides,
2- (4- benzyloxy-phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- hydroxy phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- isopropyl phenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- propoxyphenyls)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
2- (4- cyclopentyloxies phenyl)-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-3- Phenylpropylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-4- methoxYbenzylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2- methoxYbenzylaminos) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2- (4- methoxyphenyl ethyls) amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2,4- Dimethoxybenzylamino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2,4,6- trimethoxy benzyl amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-4- trifluoromethyl benzyls amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-3- bromobenzyls amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N-2- (3,4,5- trimethoxyphenyl) ethylamino) -2- (4- methoxyphenyls) -2H- benzotriazole,
5- (N- (2- furfuryls) amino) -2- (4- methoxyphenyls) -2H- benzotriazole,
The chloro- N- of 1- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
The chloro- N- of 3- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-butyramide,
3- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases carbamoyl]-acrylic acid,
Trifluoromethyl-N- [2- (4- methoxyphenyls) -2H- benzotriazole -5- bases]-acetamide,
Or nitric acid 2- ((2- (4- methoxyphenyls) -2H- benzotriazole -5- bases) amino) -2- oxoethyl esters.
4. according to any one of them benzotriazole compound or its pharmaceutically acceptable salt of claims 1 to 3, its It is characterized in that, the benzotriazole compound pharmaceutically acceptable salt is by the benzotriazole compound and sour shape Into acid-addition salts；Wherein, the acid is：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, first sulphur Acid, p-methyl benzenesulfonic acid, lactic acid, pyruvic acid, maleic acid or butanedioic acid.
5. a kind of method for preparing benzotriazole compound pharmaceutically acceptable salt as claimed in claim 4, it is special Sign is, the described method comprises the following steps：
(1) benzotriazole compound is dissolved in the first organic solvent；
(2) acid is dissolved in the second organic solvent；
(3) above two solution is sufficiently mixed in proportion, place 10 minutes to 8 it is small when after, obtain the benzotriazole Compound pharmaceutically acceptable salt.
Wherein, first organic solvent and the second organic solvent include methanol, ethanol, acetone, acetonitrile, ether, dichloro respectively One or more in methane, chloroform, ethyl acetate, dioxane and glycol dimethyl ether；
It is described acid include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid, to toluene sulphur One kind in acid, lactic acid, pyruvic acid, maleic acid and butanedioic acid.
A kind of 6. pharmaceutical composition, it is characterised in that any one of them benzotriazole comprising such as claims 1 to 3 Compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
7. pharmaceutical composition according to claim 6, it is characterised in that the formulation of described pharmaceutical composition include fluid, Aerosol, emulsifiable paste, gelling agent, pill, capsule, syrup, transdermal patch or excipient.
8. existed according to any one of them benzotriazole compound of claims 1 to 3 or its pharmaceutically acceptable salt Prepare the purposes in prevention and treatment medicine of disease as caused by RAS gene mutations.
9. existed according to any one of them benzotriazole compound of claims 1 to 3 or its pharmaceutically acceptable salt Prepare the purposes on the antitumor drug of prevention and treatment targeting RAS gene mutations.
10. existed according to any one of them benzotriazole compound of claims 1 to 3 or its pharmaceutically acceptable salt Prepare the recurrence medicine of the prevention and treatment propagation of tumour cell, growth, migration and infiltration as caused by RAS gene mutations or tumour Purposes in thing.
11. the purposes as described in claim 9 or 10, it is characterised in that the tumour is the induction as caused by RAS gene mutations The tumour of property or acquired resistance.
12. the purposes according to claim 9 or 10, it is characterised in that the tumour is malignant tumour, including lung cancer, intestines Cancer, cancer of pancreas, breast cancer, uterine cancer, multiple bone marrow cancer, stomach cancer, oophoroma, carcinoma of urinary bladder, prostate cancer, cervical carcinoma, nerve Glioma.
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